The glucocorticoid receptor (GR) is a steroid hormone receptor which belongs to the nuclear receptor superfamily (nuclear receptor subfamily 3, group C, member 1). GR is encoded by gene NR3C1 on chromosome 5 (5q31). GR plays an important role in many physiologic processes, such as regulating glucose and lipid metabolism, bone development, and maintaining body salt balance.
GR exerts its physiologic roles through binding to its ligand (e.g. corticoid). The activated form of GR has two principal mechanisms of action: transactivation and transrepression of target gene expression. “Transactivation” is a direct mechanism of action involves homodimerization of GR, translocation via active transport into the nucleus, and binding to specific DNA responsive elements, thereby activating gene transcription. In transrepression, GR does not directly bind to target DNA, instead, GR is tethered to other transcriptional factors, such as NF-kB or AP-1, by protein-protein interaction, thereby repressing the transcriptional activity of the tethered transcriptional factors, e.g., NF-kB transcriptional activity on IL-6, IFN-b, ICAM1 etc genes.
GR is a target for treating anti-inflammatory and self-immune diseases, such as rheumatoid arthritis, asthma, allograft rejection, and allergic skin diseases. Treatment is based on the transrepression properties of GR on major proinflammatory cytokines, such as TNF-alpha, IL-8, IL-6 and IL-1 beta. GR also has transrepression properties with respect to NF-kB. NF-kB is not a proinflammatory cytokine, but is a master regulator of proinflammatory cytokines, i.e., it can induce many proinflammatory cytokines, such as IL-1b, IL-6, IL-8, IFN-b. Usually the activation of NF-kB occurs at the onset of inflammation.
GR also is an important target for treating leukemia, especially Childhood Acute Lymphoblastic Leukemia (ALL). This treatment is based on inducing apoptosis in leukemia cells with a corticoid-like GR agonist, such as dexamethasone (DEX).
Unfortunately, corticoid-like drugs can result in side effects because of the unwanted transactivation activity of GR. As such, long term use of corticoid-like drugs can lead to diabetes, osteoporosis, skin atrophy, and growth retardation. Thus, an important issue for corticoid-like anti-inflammatory drug discovery is to identify a GR ligand which can retain or increase GR transrepression activity, but with only minimal remaining GR transactivation activity. Such a GR ligand is called a “dissociated GR ligand”. However, all of the known attempts to identify a dissociated GR ligand have resulted in a GR ligand that either (a) retains only a very small part of its transrepression activity, or (b) has significant transactivation activity, e.g., undesirable side effects. As such, none of these known compounds has been used in a clinical setting to date.